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Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice
Sonya S Glasson1, Roger Askew, Barbara Sheppard
1Wyeth Research, Cambridge, Massachusetts 02140, USA.
Objective:
To determine the importance of the enzymatic activity of ADAMTS-4 in normal growth and development and to evaluate the role of ADAMTS-4 in the progression of osteoarthritis (OA).
Methods:
We generated catalytic domain-deleted ADAMTS-4-transgenic mice and performed extensive gross and histologic analyses of various organs. The mice were challenged by surgical induction of joint instability leading to OA, to determine the importance of the enzymatic activity of ADAMTS-4 in the progression of the disease. The response of wild-type (WT) and ADAMTS-4-knockout (ADAMTS-4-KO) articular cartilage to interleukin-1 and retinoic acid challenge in vitro was also evaluated.
Results:
ADAMTS-4-KO mice up to 1 year of age exhibited no gross or histologic abnormalities in 36 tissue sites examined. Despite evidence of ADAMTS-4 expression and activity in growth plates of WT mice, catalytic silencing of this proteinase caused no abnormalities in skeletal development, growth, or remodeling. There was no effect of ADAMTS-4 knockout on the progression or severity of OA 4 weeks or 8 weeks after surgical induction of joint instability. Enzymatic cleavage of aggrecan at the TEGE(373-374)ARGS site was clearly evident after exposure of articular cartilage from ADAMTS-4-KO mice to inflammatory cytokines.
Conclusion:
Although expression of the ADAMTS-4 gene has been found in many tissues throughout the body, deletion of enzymatic activity did not appear to have any effect on normal growth and physiology. Our study provides evidence that ADAMTS-4 is the primary aggrecanase in murine growth plates; however, deletion of its enzymatic activity did not affect normal long bone remodeling. Our results also lead to the hypothesis that, in the mouse, ADAMTS-4 is not the primary enzyme responsible for aggrecan degradation at the TEGE(373-374)ARGS site. The elucidation of the relative importance of ADAMTS-4 in the pathologic process of human OA will require examination of human OA tissues and evidence of disease modification in patients following therapeutic intervention.
Insights
Enzymatic activity of ADAMTS-4 is not essential for normal growth or osteoarthritis progression in mice. Deleting ADAMTS-4 activity did not impact skeletal development or joint disease, suggesting other enzymes play a key role.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) is implicated in extracellular matrix degradation.
- Its role in normal physiological processes and osteoarthritis (OA) pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the necessity of ADAMTS-4 enzymatic activity for normal growth and development.
- To assess the contribution of ADAMTS-4 to the progression of osteoarthritis.
Main Methods:
- Generated catalytic domain-deleted ADAMTS-4-transgenic mice.
- Conducted gross and histological analyses of multiple organs.
- Induced surgical joint instability to model OA and evaluated disease progression.
- Assessed wild-type and ADAMTS-4-knockout articular cartilage response to inflammatory stimuli in vitro.
Main Results:
- ADAMTS-4 knockout mice showed no abnormalities in 36 examined tissue sites up to one year of age.
- Absence of ADAMTS-4 enzymatic activity did not affect skeletal development, growth, or remodeling, despite its presence in growth plates.
- ADAMTS-4 knockout did not alter the severity or progression of surgically induced osteoarthritis.
- Aggrecan cleavage at the TEGE(373-374)ARGS site occurred in knockout cartilage exposed to inflammatory cytokines, indicating redundant enzymatic activity.
Conclusions:
- ADAMTS-4 enzymatic activity is dispensable for normal murine growth and physiology.
- ADAMTS-4 is the primary aggrecanase in murine growth plates, but its absence does not impact long bone remodeling.
- ADAMTS-4 is likely not the primary enzyme responsible for aggrecan degradation at the TEGE(373-374)ARGS site in mice.
- Further studies on human OA tissues and therapeutic interventions are needed to clarify ADAMTS-4's role in human osteoarthritis.
